Epithelial cells lining exposed mucosal surfaces, such as the gastrointestinal, respiratory, and genito-urinary tracts, express the polymeric immunoglobulin receptor (pIgR). The pIgR binds to IgA at the basolateral surface of the epithelial cell. The pIgR-IgA complex is endocytosed, transcytosed, and the IgA is released at the apical surface of the cell. The IgA discharged into secretions forms the first immunological defense against mucosal infections, which account for >95% of human infectious diseases. Mucosal infections include many high priority diseases, such as AIDS and AIDS-associated infections, emerging and re-emerging diseases such TB and multiple antibiotic resistant bacteria, and biological warfare/terrorist agents (including inhalational anthrax). Moreover, it was recently discovered that as the IgA is being transcytosed across the cell, it can neutralize viruses within the cell, and that this is a major mechanism of antiviral immunity. Also, the major bacterial pathogen, S. pneumoniae, uses the pIgR to enter and transcytose across nasopharyngeal cells, leading to disseminated infection. The most effective strategy for control of mucosal infections is mucosal vaccination. The goal of this research is to understand the molecular mechanism of transcytosis of IgA. This is crucial to understanding the mucosal immune response and the development of mucosal vaccines. The role of syntaxins in targeting movement of pIgR specifically to the apical and basolateral surfaces of epithelial cells will be analyzed. The role of the mammalian retromer complex in trafficking of the pIgR will be determined. The mechanism by which the recently discovered GGA3 protein directs pIgR traffic will be dissected.